Tregs prevent CD8s from killing virus-infected cells & 3/04 Immunity
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Contact: Heidi Hardman
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Cell Press
Adaptive regulatory T cells suppress killing of persistently infected
cells
Scientists report that they have identified a cellular mechanism that
prevents the immune system from destroying chronic, incurable viral
infections such as herpes, hepatitis and human immunodeficiency virus
(HIV). The research, published in the March issue of Immunity, explains
why critical immune cells fail to act against the viral infection and
demonstrates a successful intervention that facilitates elimination of
the virus. The results open up exciting new avenues for design of future
antiviral therapeutics.
Many human viruses are able to evade the immune system during acute
infection and establish long-term persistent infections that are
extremely difficult to eliminate. Most of the time, proliferation of the
virus is balanced by antiviral immunity and the host experiences little
to no damage. However, persistent infections with viruses such as HIV or
hepatitis lead to life threatening diseases that currently have no cure.
Immune cells called CD8+ T cells are critical for recovery from viral
infections and persistent viral infections are associated with a
malfunction of these cells that is not well understood. Dr. Kim J.
Hasenkrug from the Rocky Mountain Laboratories, part of the National
Institute of Allergy and Infectious Diseases at the National Institutes
of Health, and colleagues investigated persistent infection of mice with
Friend virus (FV) to look at the specific mechanisms that contribute to
CD8+ T cell dysfunction. The researchers found that although the CD8+ T
cells could recognize their appropriate targets they could not destroy
them. The key finding was that regulatory CD4+ T cells suppress the
normal function of the CD8+ T cells in the persistently infected mice.
Importantly, suppressing the activity of the regulatory CD4+ cells could
prevent dysfunction of CD8+ T cells.
The researchers conclude that CD4+ T cells contribute to viral
persistence by suppressing the host CD8+ T cell response and that
influencing the activity of CD4+ T cells can reduce this suppression.
"A practical intervention that could reduce virus loads during chronic
HIV infection would likely be an invaluable tool in postponing the onset
of AIDS. While it remains to be seen whether an intervention such as
described in our study would work in HIV infections, our experiments
open new possibilities of therapy for treating persistence, one of the
most refractory elements of retroviral infections," explains
Dr.Hasenkrug.
Ulf Dittmer, Hong He, Ronald J. Messer, Simone Schimmer, Anke R.M.
Olbrich, Claes Ohlen, Philip D. Greenberg, Ingunn M. Stromnes, Michihiro
Iwashiro, Shimon Sakaguchi, Leonard H. Evans, Karin E. Peterson, Guojun
Yang, and Kim J. Hasenkrug: "Functional Impairment of CD8+ T Cells by
Regulatory T Cells during Persistent Retroviral Infection"
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Published in Immunity, Volume 20, Number 3, March 2004, pages 293-304.
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Immunity, Vol 20, 293-303, March 2004
Functional Impairment of CD8+ T Cells by Regulatory T Cells during
Persistent Retroviral Infection
Ulf Dittmer 2, Hong He 1, Ronald J. Messer 1, Simone Schimmer 2, Anke
R.M. Olbrich 2, Claes Ohlen 3, Philip D. Greenberg 3, Ingunn M. Stromnes
15, Michihiro Iwashiro 16, Shimon Sakaguchi 4, Leonard H. Evans 1, Karin
E. Peterson 1, Guojun Yang 1, and Kim J. Hasenkrug *1
1Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories,
National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Hamilton, MT 59840 USA
2Institut für Virologie des Universitätsklinikums, 45122 Essen, Germany
3Department of Medicine and Immunology, University of Washington,
Seattle, WA 98195 USA
4Department of Experimental Pathology, Institute for Frontier Medical
Sciences, Kyoto University, Kyoto, 606-8507, Japan Correspondence:
Kim J. Hasenkrug
406-363-9310 (phone)
406-363-9204 (fax)
khase...@nih.gov
Abstract: The establishment of viral persistence generally requires
evasion of the host CD8+ T cell response. Here we describe a form of
evasion wherein the CD8+ T cells are fully capable of recognizing their
cognate antigen but their effector functions are suppressed by
regulatory T cells. Virus-specific CD8+ T cells adoptively transferred
into mice persistently infected with Friend virus proliferated and
appeared activated, but failed to produce IFN-gamma or reduce virus
loads. Cotransfer experiments revealed that a subpopulation of CD4+ T
cells from persistently infected mice suppressed IFN-gamma production by
the CD8+ T cells. Treatment of persistently infected mice with anti-GITR
antibody to ameliorate suppression by regulatory T cells significantly
improved IFN-gamma production by transferred CD8+ T cells and allowed a
significant reduction in viral loads. The results indicate that CD4+
regulatory T cells contribute to viral persistence and demonstrate an
immunotherapy for treating chronic retroviral infections.